The glypican family has been reported to be present as a new family of heparan sulfate proteoglycans that are present on cell surfaces. To date, the 5 types of glypicans (glypican 1, glypican 2, glypican 3, glypican 4 and glypican 5) have been reported as members of the glypican family. These members of the family have core proteins of uniform size (approximately 60 kDa), share specific and well-conserved cysteine sequences, and bind to cell membranes via glycosyl phosphatidyl inositol (GPI) anchors.
A Dally (division abnormally delayed) gene has been identified by screening for genes of a variant of Drosophila melanogaster having an abnormal cell division pattern in the development of the central nervous system. The cDNA of Dally is known to represent an open reading frame (ORF) encoding a product having a sequence that shows homology (24 to 26% homology) with a membrane-spanning proteoglycan (GRIPs) of a vertebrate containing all the features of a glypican. It has been then suggested that the dally gene plays a role in regulating the dpp (decapentaplegia) receptor mechanism. This suggests that the glypican of a mammal may regulate the signal transduction between TGF and BMP. Specifically, it has been suggested that glypican may function as a common receptor for some of heparin-binding growth factors (e.g., EGF, PDGF, BMP2 and FGF's).
Glypican 3 has been isolated as a transcript under developmental regulation in rat intestine (Filmus, J., Church, J. G., and Buick, R. n. (1988) Mol. Cell Biol. 8, 4243-4249), and then identified as OCT-5, a GPI-linked heparan sulfate proteoglycan of the glypican family, which has a core protein with a molecular weight of 69 kDa (Filmus, J., Shi, W., Wong, Z.-M., and Wong, M. J. (1995) Biochem. J. 311, 561-565). Also in humans, a gene encoding glypican 3 has been isolated as MXR-7 from a human gastric cancer cell line (Hermann Lage et al., Gene 188 (1997) 151-156). Glypican 3 has been reported to form a protein-protein complex with an insulin-like growth factor-2 so as to regulate the action of the growth factor (Pilia, G. et al, (1996) Nat. Genet. 12, 241-247). This report suggests that glypican 3 does not always interact with growth factor having the heparan sulfate chain.
There has been a report suggesting that glypican 3 may be utilized as a hepatic cancer marker (Hey-Chi Hsu et al., CANCER RESEARCH 57, 5179-5184 (1997)). However, there is no finding indicating a clear relationship between glypican 3 and the proliferation of carcinoma cells.
Moreover, it has also been suggested that glypican may function as a receptor for endostatin that may act as a vascularization inhibitor (Molecular Cell (2001), 7, 811-822). However, the relationship between this function and cell proliferation has not been elucidated either.
As described above, the involvement of glypican 3 in cell proliferation has been suggested. However, the cell proliferation mechanism and the like are unknown, and the application of glypcian 3 for the regulation of cell proliferation has never been attempted.